DESCRIPTION (Verbatim from the Applicant's Abstract): The long term goal of this proposed research is to test the hypothesis that protease-activated receptors (PARs) and their serine protease ligands may play significant roles in the pathology of the nervous system, including neuron degeneration and death. There is increasing evidence suggesting that, in addition to their role in blood coagulation, serine proteases such as thrombin prevent normal differentiation of glial cells and induce neuronal cell death. The effects of thrombin-like proteases are known to be mediated through PARs expressed on the cell surface. In addition, it has been recently reported that the genes for two members (PAR-1 and PAR-2) of this family of receptors are tightly linked on chromosome 5q13, which is in close proximity to the spinal muscular atrophy gene locus. More recently, it has been shown that the wobbler mouse, a suggested animal model for motoneuron disease, exhibits an increased PAR-1 expression in the spinal cord. Together, these observations support the idea that perturbed expression or activation of PARs may be associated with motoneuron disease. However, the roles that these receptors play in the nervous system are still not well understood. In the present proposal, we will examine the effects of PAR-1, PAR-2 and PAR-3 on chick spinal motor neurons in vitro and in vivo. We will also examine the developmental expression of these receptors as well as their regulation following injury. Using an in vitro culture system, we will begin to examine the cellular and molecular mechanisms by which activation of these receptors affects motoneuron survival and differentiation and whether these effects can be reversed by different neurotrophic factors. These studies may be especially significant in understanding normal development of the nervous system as well as in determining the function of PARs in spinal motoneuron degeneration. Our findings may also provide insights into the mechanisms of disease such as spinal muscular atrophy and amyotrophic lateral sclerosis.